A Prospective Study of CPAP Therapy in Relation to ...

Article

A Prospective Study of CPAP Therapy in Relation to Cardiovascular Outcome in a Cohort of Romanian Obstructive Sleep Apnea Patients

Ioana Maria Chetan 1,2, Anca Diana Maierean 1,*, Bianca Domokos Gergely 1, Georgiana Cabau 3, Raluca Tomoaia 2,4, Ana Florica Chis 1, Adriana Albu 5, Mirela Anca Stoia 6, Stefan Cristian Vesa 7, Dan Blendea 8, and Doina Adina Todea 1,

Citation: Chetan, I.M.; Maierean, A.D.; Domokos Gergely, B.; Cabau, G.; Tomoaia, R.; Chis, A.F.; Albu, A.; Stoia, M.A; Vesa, S.C.; Blendea, D.; et al. A Prospective Study of CPAP Therapy in Relation to the Cardiovascular Outcome in a Cohort of Romanian Obstructive Sleep Apnea Patients. J. Pers. Med. 2021, 11, 1001.

Academic Editor: Konstantinos Tziomalos

Received: 21 September 2021 Accepted: 30 September 2021 Published: 2 October 2021

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Copyright: ? 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ().

1 Department of Pneumology, "Iuliu Hatieganu" University of Medicine and Pharmacy, 400332 Cluj-Napoca, Romania; mariaioana_25@ (I.M.C.); biancadomokos@ (B.D.G.); anna_f_rebrean@ (A.F.C.); doina_adina@ (D.A.T.)

2 Heart Institute "Nicolae Stancioiu", 400001 Cluj-Napoca, Romania; raluca.tomoaia@ 3 Department of Medical Genetics, "Iuliu Haieganu" University of Medicine and Pharmacy,

400349 Cluj-Napoca, Romania; georgiana.cabau@ 4 Department of Cardiology, "Iuliu Hatieganu" University of Medicine and Pharmacy,

400437 Cluj-Napoca, Romania 5 2nd Internal Medicine Department, "Iuliu Hatieganu" University of Medicine and Pharmacy,

400000 Cluj-Napoca, Romania; adriana.albu@umfcluj.ro 6 Department of Internal Medicine, "Iuliu Hatieganu" University of Medicine and Pharmacy,

400006 Cluj-Napoca, Romania; mirelastoia@ 7 Department of Pharmacology, Toxicology and Clinical Pharmacology, "Iuliu Hatieganu" University of

Medicine and Pharmacy, 400337 Cluj-Napoca, Romania; stefanvesa@ 8 Department of Medicine, Faculty of Medicine, "Iuliu Hatieganu" University of Medicine and Pharmacy,

400337 Cluj-Napoca, Romania; dblendea1@ * Correspondence: anca.lupascu91@ Author with equally contribution to this work.

Abstract: Background: Despite efforts at treatment, obstructive sleep apnea (OSA) remains a major health problem, especially with increasing evidence showing an association with cardiovascular morbidity and mortality. The treatment of choice for OSA patients is Continuous Positive Airway Pressure (CPAP), which has been proven in randomized controlled trials to be an effective therapy for this condition. The impact of CPAP on the cardiovascular pathology associated with OSA remains, however, unclear. Although the effect of CPAP has been previously studied in relation to cardiovascular outcome, follow-up of the treatment impact on cardiovascular risk factors at one year of therapy is lacking in a Romanian population. Thus, we aimed to evaluate the one-year effect of CPAP therapy on lipid profile, inflammatory state, blood pressure and cardiac function, assessed by echocardiography, on a cohort of Romanian OSA patients. Methods: We enrolled 163 participants and recorded their baseline demographic and clinical characteristics with a follow-up after 12 months. Inflammatory and cardiovascular risk factors were assessed at baseline and follow up. Results: Our results show that CPAP therapy leads to attenuation of cardiovascular risk factors including echocardiographic parameters, while having no effect on inflammatory markers. Conclusion: Treatment of OSA with CPAP proved to have beneficial effects on some of the cardiovascular risk factors while others remained unchanged, raising new questions for research into the treatment and management of OSA patients.

Keywords: cardiovascular disease; CPAP; obstructive sleep apnea syndrome; serum lipids; tricuspid annular plane systolic excursion

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1. Introduction

Obstructive sleep apnea (OSA) is a common sleep disorder that affects about 4?7% of the general adult population, with reported global prevalence of 1 billion persons affected and an estimated prevalence exceeding 50% in some countries. In Romania, data regarding the clinical features of OSA, and mainly the burden of comorbidities, are lacking. According to a recent study, the estimated prevalence of OSA in Romania is 48.1% [1,2]. Presence of recurrent partial or complete collapse of the upper airway during sleep, leading to chronic intermittent hypoxia, is the main characteristic of the disease [3]. Among known risk factors for sleep apnea, some are also risk factors well established for cardiovascular disease (CVD). There is growing evidence demonstrating that OSA patients have an increased risk of cardiovascular morbidity and mortality [4]. OSA has been associated with different forms of cardiovascular disease including heart failure, hypertension, arrythmias, stroke and coronary artery disease [5]. Despite the fact that there is a strong connection between CVD and OSA, randomized clinical trials are yet to show that treating OSA improves cardiovascular outcomes [6]. There is very limited data from randomized trials, which have been limited in number and design [7].

Pathophysiologic mechanisms connecting OSA with CVD include oxidative stress, endothelial dysfunction, increased sympathetic nervous system activity, predilection for hypertension, dyslipidemia and metabolic dysregulation (insulin resistance) [8]. OSA treatment has been proved to diminish these processes, offering a feasible mechanism by which therapy could influence cardiovascular (CV) outcomes [9].

Efficient management of OSA includes a comprehensive assessment of each individual's characteristics, as well as monitoring and follow-up. Continuous positive air pressure (CPAP) therapy is a first-line treatment for all patients diagnosed with OSA. It is cost effective and has been shown to both reduce apnea/hypopnea index (AHI) and improve quality of life [10]. Nevertheless, CPAP continues to be affected by adhesion problems. Results of an extensive analysis based on the literature suggest that, despite many interventions planned to improve adherence rates over the long term, trends show no clinical changes on its impact, with a high nonadherence of 30?40% [11]. Early retrospective trials supported the effectiveness of OSA therapy in enhancing CV outcomes. [12?14]. The SAVE (Sleep Apnea Cardiovascular Endpoints) trial was the largest randomized control trial (RCT) done to evaluate whether CPAP therapy could improve CV outcomes in subjects with established CVD [6]. The trial did not demonstrate any significant reduction in the primary end points (composite of CV death, myocardial infarction, stroke, hospitalization, heart failure (HF) or transient ischemic attack), although significant/notable improvements were obtained in health-related quality of life, snoring and daytime sleepiness.

While CPAP therapy seems to be successful in reducing OSA symptoms, the findings of randomized trials, so far, do not support its effectiveness in reducing the risk of CV events in OSA patients [15]. Thus, these limitations may serve as topics of interest for future investigations. Furthermore, the Romanian National Health Insurance System does not reimburse the costs related to the investigation and management of OSA, so many patients remain undiagnosed, and without treatment, due to the costs.

We hypothesized that CPAP therapy improves lipid profile levels, along with blood pressure and RV function echocardiographic parameters. Moreover, we assumed that by identifying the effects of CPAP therapy on cardiovascular risk factors, we may improve awareness in the Romanian population about the importance of early diagnosis and subsequentl treatment of OSA, despite the costs. CPAP is the only treatment, at the present time, with evidence that supports improvement in quality of life and reduction of the burden of associated comorbidities.

Given these considerations, the objectives of our study were to provide current and reliable data regarding the effect of CPAP therapy at a one-year follow-up on cardiovascular risk factors in the OSA adult population in Romania, to estimate their prevalence, awareness and improved control.

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2. Materials and Methods

2.1. Study Population

Between January 2018 and December 2019, we examined and screened a cohort of consecutive adult patients for OSA in our Pulmonology Clinic of Cluj-Napoca. The patients were admitted to the hospital because of a history of daytime sleepiness, apnea or snoring. The study was conducted according to the guidelines of the Declaration of Helsinki and was approved by the ethics committee (number: 103/2018); all patients provided written informed consent.

Inclusion criteria for patients were age 18 years, and the presence of a minimum of three clinical symptoms of OSA. The symptoms were snoring, witnessed apneas, gasping/choking episodes, excessive sleepiness not explained by other factors, nocturia, morning headaches and decreased concentration and memory.

We excluded patients with unstable or decompensated cardiopulmonary disease, malignancy, recent surgery, physical or psychological incapacity, chronic intake of hypnotics or refusal to participate in the study.

We enrolled 205 patients in the study who met the inclusion criteria, of whom 17 declined participation in the study, 23 could not be reached and two had died from noncardiac or respiratory causes.

The patients included were divided into two groups based on necessity of CPAP therapy. The initiation of therapy was done according to Medicare guidelines as follows: all patients with an AHI greater than 15 were considered eligible for CPAP, regardless of symptomatology; for patients with an AHI of 5?14.9/h, CPAP was indicated only if the patient had one of the following: excessive daytime sleepiness, impaired neurocognitive function, mood disorders, insomnia, cardiovascular disease (e.g.,: hypertension, ischemic heart disease), or a history of stroke [16].

The first group included patients not using CPAP therapy, either because they did not match the specific criteria or because of noncompliance (non-CPAP group, n = 57). The second study group included patients who underwent CPAP therapy (CPAP group; n = 106) based on the results of a sleep study and symptomatology, as previously stated. Follow up data were collected from the 163 participants who completed the study (Figure 1).

Figure 1. Study flow chart.

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Cardiovascular risk profile was assessed at the time of first visit. This included patient's history, tobacco smoking history, medication use (lipid lowering drugs, antihypertensive agents), a physical exam, including anthropometric measurements, blood pressure, a sleep study, ECG, and echocardiography, and a blood exam (triglycerides, total cholesterol, C-reactive protein).

2.2. Sleep Study All participants underwent a cardiorespiratory sleep study using a Nox T3 polygra-

phy device, which included continuous recording from nasal cannulae, heart rate, oxygen saturation, tracheal sounds (microphone), thoracic and abdominal movement and body position. Sleep study results were analyzed and approved by trained personnel. Apnea was defined as a complete cessation of airflow lasting at least 10 s, while hypopnea was diagnosed when there was reduction in respiratory airflow of >50% lasting 10 s or longer. The absence of airflow in the presence of paradoxical thoracic or abdominal motion was diagnosed as obstructive apnea [17]. The number of events of apnea and hypopnea per hour was calculated. OSA diagnosis was established in the event that AHI was greater than or equal to 15 per hour, or greater than or equal to 5 and less than or equal to 14 events per hour with documented symptoms of unintentional sleep episodes during wakefulness; daytime sleepiness; insomnia; mood disorders; the bed partner describing loud snoring, breathing interruptions, or both, during the patient's sleep, or documented hypertension, ischemic heart disease or history of stroke, [16]. CPAP titration was made using an autoCPAP device (Philips respironics dreamstation AutoCPAP) after a validated protocol [18]. All participants received sleep hygiene advice and counseling for weight loss.

2.3. Echocardiography Standard transthoracic echocardiography and Doppler evaluation were performed

using commercially available equipment (iE33; Philips Medical Systems, Andover, MA, USA.) All measurements were assessed, as an average of three consecutive beats according to the current European and American guidelines [19]. The following measurements were performed: basal right ventricle (RV) diameter in the apical four chamber view (A4C) at the end-diastole, tricuspid annular plane systolic excursion (TAPSE) as a parameter of RV longitudinal systolic function in a standard A4C; left ventricular ejection fraction (LVEF) and mean tricuspid regurgitant gradient. The left ventricle (LV) volumes (end-systolic volume [ESV] and end-diastolic volume [EDV]) and LVEF were measured using manual tracing (biplane Simpson's) method.

2.4. Blood Pressure Assessment Blood pressure (BP) was measured in the right arm using a standard mercury sphyg-

momanometer during each day of hospitalization, and an average of the values was obtained for further analysis. During all measurements, patients were supine and awake.

2.5. Anthropometric and Biochemical Measurements Body weight and length were measured and recorded. Body mass index (BMI) was

calculated with the formula of body weight/height2 (kg/m2). The same person performed all the measurements using the same tools. Obesity was defined as a body mass index (BMI) 30 kg/m2.

In all patients, fasting blood samples were drawn at the first visit and after 12 months, to evaluate serum levels of triglycerides (TG), total cholesterol (TC) and C-reactive protein (CRP). Serum samples were analyzed according to standard laboratory methods.

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2.6. Outcome and Follow-Up

Patients had follow-up visits at 1, 6 and 12 months with clinical exams performed at each visit. Laboratory tests and a sleep study were performed at enrollment and at the 12 months follow-up visit. CPAP used at least 4 h per night for at least 70% of the days monitored was considered adequate adherence determined from CPAP tracking systems. Every medical visit considered appearance of any new medical events, changes in treatment, clinical variables and adherence to CPAP. Lipid lowering therapy and antihypertensive treatment were kept constant during the initial visit and follow up.

2.7. Statistical Analysis

Statistical analysis was performed using the MedCalc? Statistical Software version 19.7 (MedCalc Software Ltd., Ostend, Belgium; (accessed on 12 January 2021); 2021). Quantitative data were examined for normality of distribution using the Shapiro-Wilk test and were expressed as median and 25?75 percentiles. Qualitative data were expressed as frequency and percentage. Comparisons between groups were verified using the Mann-Whitney test or chi-square test, whenever appropriate. Comparison between baseline and follow-up, taking into account the treatment with CPAP, was performed with two-way ANOVA for the repeated measurements test after qualitative variables were log transformed. A "p" value lower than 0.05 was considered statistically significant.

3. Results

Median age of the study population was 59 (IQR 52.6; 65.2) with 45.6% identified as female in the non-CPAP group, and 61 (IQR 53.7; 67) with 35.8% female in the CPAP group. Among non-CPAP patients 38.6% were on treatment with lipid lowering drugs and 68.4% on antihypertensive treatment, comparative with CPAP group, where 34.9% were receiving lipid lowering drugs and 78.3% anti-hypertensive agents. Regarding smoking status, there was no significant difference at baseline between the groups, with 37 smokers in non-CPAP group (64.9%) and 57 smokers in the CPAP group (53.8%) (chi2 = 1.872, p = 0.17). The median AHI was 44.3 (IQR 22.8; 82.1) in the non-CPAP group, and 45 (IQR 32.2;65.9) in group treated with CPAP. Median BMI for the study population at baseline was 38.1 (IQR 34.4; 40.7) in the non-CPAP group and 37.5 (IQR 33.08; 41.9) in the CPAP group, without significant differences between the two groups (p = 0.44). All baseline demographic and clinical characteristics of the study population are summarized in Table 1. Differences at baseline were observed only for SBP and DBP (p < 0.001; p = 0.01, respectively).

Table 1. Baseline Characteristics of all Randomized Patients.

Variable

Age years Sex female, n, % BMI kg-m2 Additional cardiovascular risk factors:

Non-CPAP Group (n = 57, 34.9%) 59 (52.6; 65.2) 26 (45.6%) 38.1 (34.4; 40.7)

CPAP Group (n = 106, 65%) 61 (53.7; 67) 38 (35.8%) 37.5 (33.08; 41.9)

-DM type 2, n, %

18 (31.6%)

39 (36.8%)

-Arterial hypertension, n, % -Smoking, n, % -Alcohol, n, % Medication:

39 (68.4%) 37 (64.9%) 6 (10.5%)

83 (78.3%) 57 (53.8%) 10 (9.4%)

p Value 0.76 0.22 0.44

0.5 0.16 0.17 0.8

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